Obesity and Obesogen
Obesity is a serious neuroendocrine disease characterized by excess body fat. This disease is among some of the most crucial health issues around the world and it has especially exacerbated in recent years. Declared a pandemic by the World Health Organization (WHO) in 1997, obesity rates have tripled since the 1970s, and the prevalence of adult obesity in the U.S. increased from 30.5% in 2000 to 42.4% in 2018 [1]. Currently, over 40% of US adults are obese, meaning that over 100 million adults in the US alone have obesity. Furthermore, obesity is thought to be unhealthy primarily because it is associated with what are known collectively as non-communicable diseases including hypertension, type 2 diabetes, dyslipidemia, nonalcoholic fatty liver disease, and cardiovascular disease [2]. As a result, the growing obesity pandemic has never been more urgently in need of effective solutions than ever before.
For a long time, the cause of obesity has generally been attributed to the Energy Balance Model (EBM), the idea that obesity is caused by excess calories and lack of exercise, implying that our own human activity determines whether or not we obtain obesity. However, more and more studies have recently concluded that weight stability is much more complex than simply balancing energy intake versus expenditure. For instance, since 2000, obesity rates have increased while energy intake decreased and energy expenditure increased [3]. In addition, the increase in obesity has not always been restricted to humans. The EBM does not explain why numerous animal species (both in the wild, near human populations, and in captivity with controlled diets) have all gained weight over the past 25 years [4]. Furthermore, The EBM also does not explain why, for a given caloric intake or physical activity, BMI was higher in 2006 than in 1988 [5]. All these different factors suggest that there may be some external factor such as environmental chemicals that may be playing a role in obesity, impacting both animals and humans alike.
The obesogen hypothesis posits that certain chemicals, called obesogens, can interfere with the way our bodies regulate weight. One of the most widely studied obesogens is Tributyltin (TBT), which is the focus of this project. A unique aspect of TBT is its apparent transgenerational effects, which promotes obesity across multiple generations. As shown in one study by Chamorro Garcia and her team, when pregnant mice were treated with environmentally relevant (nM) doses of TBT via their drinking water, effects were detected in the F1‐F3 descendants of F0 mice exposed during pregnancy [6]. This suggests that obesogens may epigenetically influence underlying genetic mechanisms, as the DNA must have been affected if TBT results are carried transgenerationally. Currently it is very controversial which molecular mechanisms exactly underlie transgeneral inheritance of any trait.
One potential factor that may underlie transgeneral inheritance which is being explored is the role of Endogenous Retroviruses (ERVs). Human Endogenous Retroviruses (HERVs) are retroviral fossil sequences in the human genome that originated millions of years ago through retrovirus infections in germline cells and they now compose about 8% of the human genome [7]. HERV’s have been known to induce carcinogenesis, links to autoimmune diseases, and several other health issues. In an important review article, Nelson and colleagues have further outlined the potential of HERVs and other of their products to influence disease through genetic mutation, modulation and undesired expression of products [8]. We think that HERVs could be a possible explanation to why transgenerational effects of obesogens remain. Nevertheless, the mechanism of transgenerational effects is still unknown.
References:
[1] C.M. Hales, M.D. Carroll, C.D. Fryar, C.L. Ogden, Prevalence of Obesity Among Adults and Youth: United States, 2015-2016, NCHS data brief (288) (2017) 1-8.
[2] Robert H. Lustig, David Collier, Christopher Kassotis, Troy A. Roepke, Min Ji Kim, Etienne Blanc, Robert Barouki, Amita Bansal, Matthew C. Cave, Saurabh Chatterjee, Mahua Choudhury, Michael Gilbertson, Dominique Lagadic-Gossmann, Sarah Howard, Lars Lind, Craig R. Tomlinson, Jan Vondracek, Jerrold J. Heindel, Obesity I: Overview and molecular and biochemical mechanisms: United States, 2022
[3] Mozaffarian D. Perspective: obesity-an unexplained epidemic. Am J Clin Nutr. 2022;115:1445–50.
[4] Klimentidis YC, Beasley TM, Lin HY, Murati G, Glass GE, Guyton M, et al. Canaries in the coal mine: a cross-species analysis of the plurality of obesity epidemics. Proc Biol Sci. 2011;278:1626–32.
[5] Brown RE, Sharma AM, Ardern CI, Mirdamadi P, Mirdamadi P, Kuk JL. Secular differences in the association between caloric intake, macronutrient intake, and physical activity with obesity. Obes Res Clin Pract. 2016;10:243–55.
[6] Chamorro‐Garcia R, Diaz‐Castillo C, Shoucri BM, et al. Ancestral perinatal obesogen exposure results in a transgenerational thrifty phenotype in mice. Nat Commun. 2017;8:2012.
[7] Gislaine Curty, Jez L. Marston, Miguel de Mulder Rougvie, Fabio E. Leal, Douglas F. Nixon, and Marcelo A. Soares Human Endogenous Retrovirus K in Cancer: A Potential Biomarker and Immunotherapeutic Target, 2020.